Mucositis is a common, debilitating side effect of many forms of chemo- and radiation therapy used Oral mucositis results in the development of diffuse ulcerations of such severity as to necessitate changes in diet, nutritional supplementation through intravenous or gastrostomy routes, analgesic use, and dose modifications in cancer therapy. Among patients receiving myeloablative chemotherapy or head and neck radiation, mucositis was the most consistently mentioned troubling side effect of treatment mentioned by patients. Aside from its symptomatic and functional impact, oral mucositis significantly escalates the cost of care: the incremental cost of mucositis in patients with head and neck or non- small cell lung cancers is over $17,000. Despite its frequency (there will be about 450.000 new cases of oral mucositis in the U.S. this year) and health and economic burden, options for the prevention and treatment of oral mucositis are limited. Biologically active, topically-applied agents have potential, but their utility has been limited by transient mucosal resident time. To address this, for the treatment of cancer. The oral mucosa is frequently affected. we have developed inflammation responsive drug delivery hydrogel microparticles that selectively adhere to ulcers for controlled and targeted release of drugs. We developed these delivery vehicles from generally recognized as safe materials that we have coaxed, without chemical modification, to self-assemble in hydrogels that can encapsulate multiple classes of drugs during the assembly process. Here we aim to demonstrate an in vitro and in vivo proof of concept for this technology in rodent models of oral mucositis. This work will assess the hypothesis that self-assembled hydrogel microparticles containing enzyme-labile linkers can selectively adhere to the inflamed mucosa and release drugs in response to inflammation for treatment of oral mucositis. These hydrogel particles will be tested for selective adhesion, ulcer-responsive drug release, and extended duration of drug release. The hydrogel particles will also be tested with anti-inflammatory drug minocycline in the rodent models of oral mucositis. This proposal will focus on addressing the following aims: Aim 1: Characterize selective adhesion of hydrogel particles to inflamed mucosa and examine the influence of hydrogel physicochemical properties on duration of adhesion under dynamic conditions. Aim 2: Tune stimulus responsive release of model drugs from GRAS hydrogels and examine release at sites of mucosal ulcers. Aim 3: Compare the therapeutic efficacy of minocycline-loaded GRAS hydrogel microparticles versus minocycline alone administered via oral rinse in a hamster model.